Many proteins are multimeric, composed of multiple and different subunits. Expression of the respective subunits provides a critical step in the production of a functional protein. To obtain maximal production of such proteins it is important to also optimize expression levels of individual subunits. The present invention is based, in part, on the discovery that production levels and secretion of several multimeric cytokines depends not only on the absolute levels of expression, but also on the relative levels of expression of individual subunits.
Optimized ratios of the subunits resulted in greatly increased extracellular levels of the heterodimeric proteins. We have identified the optimal ratios of subunits for several heterodimeric cytokines, including IL-12 family cytokines, e.g., IL-12 chains p35 and p40, IL-23 chains p19 and p40, IL-27 chains p28 and EBI3. The use of optimized expression strategies leads to improvement of cytokine expression. This strategy is of general application for the expression of any multimeric protein.